Protein folding activity of ribosomal RNA is a selective target of two unrelated antiprion drugs.

Abstract

BACKGROUND:

6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.

METHODOLOGY/PRINCIPAL FINDINGS:

Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.

CONCLUSION/SIGNIFICANCE:

6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

• Authors: Déborah Tribouillard-Tanvier, Suzana Dos Reis, Fabienne Gug, Cécile Voisset, Vincent Béringue, Raimon Sabate, Ema Kikovska, Nicolas Talarek, Stéphane Bach, Chenhui Huang, Nathalie Desban, Sven J Saupe, Surachai Supattapone, Jean-Yves Thuret, Stéphane Chédin, Didier Vilette, Hervé Galons, Suparna Sanyal, Marc Blondel
• Journal: PloS one (PLoS One) Vol. 3 Issue 5 Pg. e2174 (May 14 2008) ISSN: 1932-6203 [Electronic] United States
• PMID: 18478094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Prions
• RNA, Ribosomal
• Guanabenz

Topics

• Blotting, Western
• Cell Line
• Chromatography, Affinity
• Electrophoresis, Polyacrylamide Gel
• Guanabenz (pharmacology)
• Prions (drug effects)
• Protein Folding
• RNA, Ribosomal (drug effects, physiology)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization